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The COMP Division is excited to announce the OpenEye Award winners for the San Francisco ACS meeting (fall 2014). Please visit the COMP award winners and the other excellent COMP posters at the COMP Poster Session on Tuesday, August 12, 2014 from 6pm to 8pm at a location to be determined.

Carbohydrates are the most diverse set of biomolecules found in nature, and they are of central importance to many aspects of cell biology including signaling, recognition, structure, and energy storage.1 As a result of their diversity and prevalence, a huge number of enzyme classes have evolved to assemble, modify, and deconstruct carbohydrates for myriad functions of life, the study of which is important for many aspects of fundamental sciences including cell biology, biochemistry, and immunity, as well as application areas such as in human health, ecology, and renewable energy.

Plants employ carbohydrates in a dramatic, prevalent manner for their function. Namely, plant cell walls comprise a self-assembled polysaccharide matrix of cellulose, hemicellulose, and pectin interspersed with the aromatic polymer, lignin. These polymers are chemically and physically linked together to protect plant cells and to provide structure which in turn imparts structure to plant tissues. Cellulose, in particular, forms the primary structural component of plants, and is the b-1,4-linked homopolymer of glucose, which forms long chains up to thousands of units long, which in turn pack into crystalline fiber bundles. Given its prevalence in plants, cellulose is the most abundant biological material on Earth, thus serves as a massive carbon sink and a food source for a huge variety of organisms. However, cellulose is in insoluble polymer that packs into dense crystals, and glycosidic bonds in polysaccharides like cellulose are 2 and 4 orders of magnitude stronger than those in DNA or peptide bonds, respectively.2 Both of these facts imply that the enzymes that deconstruct cellulose need to exhibit multiple functions including strong binding to an insoluble substrate, either binding to the substrate internal to a polymer chain or finding and complexing to a free chain end, and then decrystallizing a chain of cellulose from the polymer, cleaving a glycosidic bond, and continuing the process along the polymeric substrate. Cellulose-degrading enzymes are typically multi-modular, exhibiting at least a catalytic domain for conducting hydrolysis reactions and a carbohydrate-binding module (CBM) for binding the whole enzyme to insoluble cellulose crystals. A flexible, O-glycosylated linker typically connects these domains. Identification of the rate-limiting step in this multi-step process is of crucial importance for identifying targets for improving these enzymes, a problem of paramount importance for biofuels production.

Thomas E Markland, Department of Chemistry, Stanford University, Stanford, CaliforniaOver the past decades molecular simulation has become an increasingly important tool in predicting and interpreting chemical processes. Inherent in these simulations is the assumption that the nuclei behave classically. However, for processes involving light particles such as hydrogen the quantum mechanical nature of the particles can dramatically alter their structure and dynamics. I will present our recent advances in developing approaches to treat nuclear quantum mechanical fluctuations in condensed phase systems and to calculate isotope effects at a cost barely more than the a corresponding classical simulation. These advances allow us to investigate, in unprecedented detail, chemical systems where the inclusion of quantum mechanical effects is essential to obtain the correct result. I will illustrate the utility of these approaches with recent applications ranging from fractionation of hydrogen isotopes between liquid water and its vapor, which are a major input in climate modeling, to the biologically important proton delocalization in enzyme active sites.

Herein, we describe how a novel Non-Boltzmann Bennett reweighting scheme can be combined with the indirect QM/MM FES approach to avoid expensive QM simulations. Details of this new approach (i.e., QM-NBB) are presented with particular emphasis on connecting MM and QM levels of theory. QM-NBB is then applied to a number of test cases in explicit and implicit solvent with both absolute and relative solvation free energy differences computed. Further, QM-NBB is compared critically to the standard FEP based indirect scheme and some best practices are suggested for improving methods that seek to connect MM to QM (or QM/MM) levels of theory in FES.

Biological membranes are crucial to the life of the cell as they perform essential functions. They enclose the cell, define its boundaries and compartmentalize it. By being selectively permeable, they regulate the passage of substances into and out of cells, while at the same time they are involved in signal transduction. In this poster, several aspects of the structure and dynamics of biomembranes as well as methodologies for targeting specific membrane interfaces for developing novel drug candidates and drug delivery systems, will be presented.

Signal transduction is largely controlled by proteins embedded in or associated with membranes, which in turn are also regulated by signaling entities integral to the cell membrane such as lipid rafts. To shed light on the mechanism of the promotion of lipid rafts in eukaryotic plasma membranes and their dependence on the sterol component, we have investigated the effects of specific sterols (cholesterol, ergosterol, lanosterol) on the physical properties of membranes using Molecular Dynamics (MD) simulations. The cell membrane is often the first barrier that drugs encounter before reaching their pharmacological target. Therefore, we investigated drug-membrane interactions with MD simulations and NMR spectroscopy focusing on the modifications of membrane biophysical properties induced by drugs, which is a crucial aspect for the future design of novel drugs targeting membrane proteins. As membrane proteins and in particular ion channels may be challenging to target with small molecule inhibitors, we established a protocol that utilizes free energy perturbation (FEP)/MD calculations of relative binding free energies and desolvation free energy penalties to leave the aqueous phase and bind to a membrane protein. Finally, we discuss targeting the membrane-protein Interface with small molecule inhibitors using a variety of computational and experimental methodologies and strategies for efficiently monitoring the translocation of drug delivery systems across biological membranes.

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